The present invention relates to compounds, including derivatives of 5-pyrimidinol and 3-pyridinol and any acid or base addition salt thereof, that are effective chain-breaking antioxidants both of the lipid and water-soluble variety and, in that regard, are analogous to the natural Vitamins E and C. Hence, not only will the compounds of the present invention be excellent oxidation inhibitors as additives to fuels, lubricants, rubber, polymers, chemicals, solvents and foodstuffs, but they may also exhibit many chemopreventive effects associated with cancer, aging, heart and lung disease, inflammation, Alzheimer""s and Parkinson""s disease, skin damage and any other conditions in which free radical-mediated cellular damage or disruption is implicated and in which Vitamins E and C and other antioxidants are shown to have protective effects.
Autoxidation of hydrocarbons and other organic materials is one of the most important chemical processes known. Since the 1960""s, the mechanism of inhibition of this process by antioxidants has been extensively studied, and antioxidants are now a key additive to many hydrocarbon products, including fuels, lubricant oils, rubber, polymers, chemicals, solvents and foodstuffs. However, it has only been in the last two decades that the importance of lipid peroxidation to human health has begun to become unearthed. Since then, substantial evidence has accumulated that implicate free radicals in aging, carcinogenesis and the pathogenesis of many conditions including heart disease (e.g. atherosclerosis), lung disease (e.g. emphysema) and several neurodegenerative disorders including Alzheimer""s and Parkinson""s diseases.
Consequently, the role of both enzyme and small-molecule antioxidants and the mechanisms of their protective function have been extensively studied. For example, it is now well accepted that the key initial event in the development of atherosclerosis involves free-radical mediated oxidative modification of low-density lipoprotein (LDL).
In support of this, it has been shown that a high intake of Vitamin E (-tocopherol, Formula 1 below), a potent lipid-soluble radical-trapping antioxidant, reduces the risk of coronary heart disease and that low levels of Vitamin E in serum correlate with an increased incidence of myocardial infarction. For example, see Gey, K. F. Nutr. Biochem., 1995, 6, 206-236, incorporated herein by reference. 
Furthermore, probucol (Formula 2, below), a radical-scavenging antioxidant, is widely used to treat hypercholesterolemia and atherosclerosis. For example, see Barkley et al. Drugs 1986, 37, 761-800. 
Given that antioxidants are of such tremendous industrial importance and have also been shown to possess preventive properties on the incidence of heart disease and many other degenerative diseases, various kinds of natural and synthetic antioxidants have been synthesized and studied both in vitro and in vivo. Unfortunately, few of them have demonstrated better radical-trapping activity than xcex1-tocopherol, the major lipid-soluble radical-trapping antioxidant in plasma and LDL.
Phenols (of which xcex1-tocopherol is an example) are the most abundant and widely used natural and synthetic antioxidants. Their mechanism of action as antioxidants, relies on their ability to transfer their phenolic H-atom to a chain-carrying peroxyl radical (LOOxe2x80xa2, Reaction 1) at a rate much faster than that at which the chain-propagating step of lipid peroxidation proceeds (Reaction 2).
LOOxe2x80xa2+ArOHxe2x86x92LOOH+ArOxe2x80xa2xe2x80x83xe2x80x83Reaction 1
LOOxe2x80xa2+LHxe2x86x92LOOH+Lxe2x80xa2(+O2xe2x86x92LOOxe2x80xa2)xe2x80x83xe2x80x83Reaction 2
A higher rate for Reaction 1 is expected with an increasingly weak ArOxe2x80x94H bond, and thus as the exothermicity of Reaction 1 increases relative to Reaction 2, one would expect that ArOH becomes a better chain-breaking antioxidant. Indeed, when the logarithm of the rate constant for Reaction 1 (logk1) is plotted against the phenolic Oxe2x80x94H bond dissociation enthalpy (BDE) for several ArOH, a linear correlation of BDE (kcal/mol)=97.44-2.93 logk1(Mxe2x88x921sxe2x88x921) is obtained. This correlation can be used to predict the rate constants for the reaction of peroxyl radicals with novel phenolic compounds whose Oxe2x80x94H BDEs are known.
It is well-known that electron-donating (ED) groups substituted para and ortho to the phenolic hydroxyl lower the Oxe2x80x94H bond dissociation enthalphy (BDE) and increase the rate of H-atom transfer to peroxyl radicals. However, efforts to design new phenolic antioxidants with increased rates of H-atom transfer to peroxyl radicals have remained unsuccessful. This is because, while the substitution of phenols with increasingly ED groups (e.g., xe2x80x94NH2 and xe2x80x94NH2) decreases their Oxe2x80x94H BDEs, it also decreases their ionization potentials (IPs) such that they react directly with oxygen.
In 1985, Ingold and Burton investigated aminophenols as potential antioxidants. More specifically, they looked at Formula 3a and Formula 3b, below, as potential chain-breaking antioxidants, but found Formula 3a to be unstable in air and Formula 3b to react slowly with peroxyl radicals compared to -tocopherol. See Burton et al. J. Am. Chem. Soc. 1985, 107, 7053-7065, incorporated herein by reference. 
These results may be explained in that the steric interaction between the meta-methyl and N-ethyl groups drives the N-ethyl group down out of the plane of the ring and removes the nitrogen lone pair from conjugation with the aromatic ring. This abolishes its stabilizing effect on the aryloxyl radical.
A known problem with aminophenols as antioxidants lies not only in the fact that they are very difficult to prepare and store, but also in their toxicity. In the case of para-aminophenol, this is related to its metabolic activation (oxidation, by cytochrome P450 among other possibilities) to a reactive intermediate that reacts with nucleophilic residues on proteins or DNA to form covalent intermediate that reacts with nucleophilic residues on proteins or DNA to form covalent intermediates or that can result in the depletion of glutathione stores.
Further substituted aminophenols (such as 4-N,N-dialkylaminophenol or 4b, above) are toxic because their oxidation no longer requires metabolism, but only a direct reaction with molecular oxygen to yield superoxide and the electrophilic species. This makes the compound a pro-oxidant and possible mutagen/carcinogen/teratogen rather than an antioxidant.
Based upon the above observations, the present inventors decided that a reasonable set of design criteria for new aminophenolic antioxidants are compounds with: (1) low phenolic Oxe2x80x94H BDEs such that they have large logk1 value, but (2) high ionization potentials (IPs) such that they are not reactive to molecular oxygen.
U.S. Pat. No. 4,554,276 to LaMattina discloses 2-amino-5-hydroxy-4-methyl pyrimidines that are disclosed as being useful as inhibitors of leukotriene synthesis and for the treatment of pulmonary, inflammatory and cardiovascular diseases, cancer and psoriasis, and peptide ulcers.
U.S. Pat. No. 4,711,888 to Walker discloses hydroxy or alkoxy pyrimidines that are disclosed as being inhibitors of leukotriene synthesis and, as a result, are useful in the treatment of pulmonary, inflammatory, allergic, cardiovascular diseases, and peptide ulcers.
U.S. Pat. No. 5,187,175 to Belliotti et al., discloses 2-carbonyl subtituted-5-hydroxy-1,3-pyrimidines that are disclosed as being useful as inhibitors of 5-lipoxygenase, and thereby providing a treatment for inflammation, arthritis, pain, fever, and the like.
U.S. Pat. No. 5,196,431 to Belliotti discloses 2-substituted amino-4,6-di-tertiarybutyl-5-hydroxy-1,3-pyrimidines described as having activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment for inflammation, arthritis, pain, and fever.
U.S. Pat. No. 5,220,025 to Belliotti et al. is a divisional of the ""431 patent discussed above.
U.S. Pat. No. 5,001,136 to Walker discloses 2-substituted methylamino-amino 5-(hydroxy or alkoxy) pyridines useful in the treatment of pulmonary, inflammatory, dermatological, allergic and cardiovascular diseases.
U.S. Pat. No. 5,284,949 to Belliotti et al. discloses 2-substituted amino-4,6-di-tertiarybutyl-5-hydroxy-1,3-pyrimidines described as having activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment for inflammation, arthritis, pain, and fever.
U.S. Pat. No. 5,177,079, to Connor et al. describe 2-substituted-4,6-di-tertiary-butyl-5-hydroxyl-1,3-pyrimidines disclosed as being useful as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever.
The present invention relates to compounds, including derivatives of 5-pyrimidinol and 3-pyridinol and any acid or base addition salt thereof, that are effective chain-breaking antioxidants both of the lipid and water-soluble variety, and in that regard, are analogous to natural Vitamin E and C.
The present inventors have discovered that many 5-pyrimidinol and 3-pyridinol derivatives act as effective chain-breaking antioxidants in vitro. Their synthesis precludes that they may be prepared easily as either of the lipid- or water-soluble variety (analogous to the natural Vitamins E and C). Furthermore, compounds of the present invention may be significantly more reactive toward peroxyl radicals than the most potent form of Vitamin E (xcex1-tocopherol). Furthermore, the compounds of the present invention are stable to air oxidation. In addition to their industrial applications, compounds of the present invention exhibit many chemopreventive effects associated with cancer, aging, heart and lung disease, inflammation, Alzheimer""s and Parkinson""s disease and any other conditions in which free radicals are implicated as being involved in their pathogenesis.
Additionally, the compounds of the present invention are excellent oxidation inhibitors as additives to fuels, lubricants, rubber, polymers, chemicals, solvents and foodstuffs.
Accordingly, an object of the present invention is to provide a compound of the following formula, and acid or base addition salts thereof: 
wherein,
R1 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, N,N-dialkylamino;
R2 is selected from the group consisting of hydrogen, alkyl; and
R3 is an electron-donating substituent.
Another object of the present invention is to provide a compound of the following formula, and acid or base addition salts thereof: 
wherein,
R1 is selected from the group consisting of hydrogen, and, alkyl;
R2 is selected from the group consisting of hydrogen, and alkyl;
R3 is selected from the group consisting of hydrogen, and alkyl; and
R4 is an electron-donating substituent.
Another object of the present invention is to provide a compound of the following formula, and acid or base addition salts thereof: 
wherein,
X is Nxe2x80x94R5 or O;
R1 is selected from the group consisting of hydrogen, and, alkyl;
R2 is selected from the group consisting of hydrogen, alkyl;
R3 is selected from the group consisting of hydrogen, alkyl;
R4 is selected from the group consisting of hydrogen, alkyl;
R5 is selected from the group consisting of hydrogen, alkyl; and
n is 1 or 2.
Another object of the present invention is to provide a method of inhibiting the oxidation of compounds or mixtures comprising the addition of an effective amount of at least one of the above compounds to the compound or mixture.
Another object of the present invention is to provide a method of reducing the oxidative environment in a petroleum composition selected from the group consisting of lubricating compositions and liquid organic fuels, said method comprising adding to said petroleum composition an effective amount of an antioxidant composition, said antioxidant composition comprising at least one of the above compounds.
Another object of the present invention is to provide a method of inducing antioxidant activity in warm-blooded animals comprising administering to warm-blooded animals an antioxidatingly effective amount of a biologically active composition, the biologically active composition comprising at least one of the above compounds.
Finally, another object of the present invention is to provide a method of treating free radical-mediated cellular damage in warm-blooded animals, comprising administering to warm-blooded animals an antioxidatively effective amount of at least one of the above compounds.